PROJECT 2 PROJECT SUMMARY The goal of Project 2 in this PPG is to understand renal cellular metabolic mechanisms of salt-sensitive hypertension. Recent work, including work in this project in the current cycle of PPG, has discovered a novel role of fumarase (Fh1) and fumarate metabolism in hypertension in the Dahl salt-sensitive (SS) rat. Fumarase primarily catalyzes the conversion of fumarate to malate in the tricarboxylic acid (TCA) cycle in mitochondria. Fumarase enzyme activity is lower in the kidneys of SS rats than SS.13BN or Sprague-Dawley (SD) rats, and fumarate is higher and malate is lower in the kidneys of SS rats. Transgenic over-expression of fumarase on the background of SS rat (SSTgFh1) attenuates hypertension. Intravenous infusion of a fumarate precursor in SS.13BN rats exacerbates hypertension. It remains unknown 1) what mechanisms mediate the effect of fumarase-related metabolites on salt-sensitive hypertension, and 2) whether blood pressure salt-sensitivity in humans is associated with abnormalities in intermediary metabolism. Aim 1 of the proposed study will test a novel hypothesis that fumarase insufficiency contributes to salt-sensitive hypertension in SS rats in part by reducing arginine regeneration and nitric oxide (NO) levels in the kidney. Aim 2 studies are designed to identify metabolites associated with blood pressure in humans on low- or high-sodium intake. The proposed study could provide novel insights into the mechanisms by which fundamental metabolism contributes to hypertension. In addition, it could identify specific metabolic intermediaries that might be important for mediating the effect of dietary salt intake on blood pressure in humans.